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Endothelial cell–based systemic gene therapy of metastatic melanoma

Cancer Gene Therapy volume 8, pages 636–648 (2001)Cite this article

Abstract

Cancer metastasis accounts for a significant proportion of morbidity and mortality in patients. Effective means of treating disseminated disease remains elusive. The purpose of this study was to determine whether genetically modified endothelial cells (GMEC) can selectively target and deliver recombinant therapeutic molecules to sites of tumor metastases. Following the establishment of lung metastases of 4T1 mammary tumor in mice, intravenously (i.v.) administered, lacZ transgene–expressing endothelial cells ( lacZ -GMEC) accumulated at the tumor sites. An average of 32% and 90% of the pulmonary metastases were X-gal stained following one and three tail vein injections of 105 lacZ -GMEC, respectively. The linear pattern of X-gal staining seen within the tumor sites and the histological appearance of the tumor vasculature were consistent with the incorporation of lacZ -GMEC into blood vessels. In C57Bl/6 mice harboring lung metastases of melanoma, the administration of three sequential i.v. injections of 105 endothelial cells expressing a human interleukin 2 transgene abrogated the tumor metastases and prolonged survival of the animals. These results demonstrate that i.v.-administered GMEC can selectively accumulate, survive, and stably express exogenous genes at multiple tumor sites. These findings support a role for i.v.-administered GMEC as a potential therapeutic strategy for the systemic treatment of cancer metastases. Cancer Gene Therapy (2001) 8, 636–648.

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Acknowledgements

This work was supported by National Institutes of Health Grants CA53922 (to J.A.Z.), 5-P50-CA58185 (to J.O.O.), and the Department of Defense Grant DAMD17-98-1-8094 (to J.O.O.). We are grateful to Alex MacPherson for technical assistance with the construction of the retroviral vectors and packaging cell lines, Steven Albelda, for assistance with CD31 staining, Bryan Cullen for the human IL-2 cDNA, Dusty Miller for the PA317 packaging cells and LNCX vector, Arthur Bank for the GP+E86 packaging cells, Owen Blair and Karen Creswell of the Flow Cytometry/Cell Sorting Core, and Ann Murray of the Animal Core, for their technical assistance provided through the Lombardi Cancer Center Shared Cores Grant P30 CA-51008.

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Authors and Affiliations

  1. Department of Oncology, Georgetown University Medical Center and Vincent T. Lombardi Cancer Center, N.W. Washington, 20007, District of Columbia, USA

    John O Ojeifo, Hyeran R Lee & Ning Su

  2. Department of Pathology, Georgetown University Medical Center and Vincent T. Lombardi Cancer Center, N.W. Washington, 20007, District of Columbia, USA

    Phyllis Rezza

  3. Division of Cancer Treatment and Diagnosis, Biologics Evaluation Section, Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Rockville, 20852, Maryland, USA

    James A Zwiebel

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  1. John O Ojeifo
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Correspondence to James A Zwiebel.

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Ojeifo, J., Lee, H., Rezza, P. et al. Endothelial cell–based systemic gene therapy of metastatic melanoma. Cancer Gene Ther 8, 636–648 (2001). https://doi.org/10.1038/sj.cgt.7700356

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